Glaucoma, which some estimate affects 2 million adults over 40, is an impairment of vision caused by too much fluid pressure within the eye.
Surgical treatment for glaucoma is effective; however, it is expensive and some surgeons will use surgery only as a last resort.
Carbonic anhydrase inhibitors, prescribed orally, work well to treat this disease, but they carry a host of side effects, from nausea to kidney stones.
Glaucoma stems from an excess of fluid behind the cornea, the three-layered tissue that acts as a window to let light enter. Fluid carrying nutrients such as potassium and glucose constantly wash the inside of the cornea to keep it healthy, much as tears wash the outside of the cornea.
In some middle-aged adults, fluids build up faster than can be absorbed back into the blood, for one of two reasons: the ciliary body (a tiny tissue behind the iris) may excrete too much fluid, or the fluid may not drain off at the normal rate.
Either way, the excess fluid damages the optic nerve. At first a glaucoma victim usually experiences a subtle loss of peripheral vision--objects will seem to disappear from certain spots to the side. But glaucoma often leads to middle-age blindness.
Unfortunately, the two approaches to general drug usage in treating glaucoma--topical (dropped into the eye) and oral--each have a peculiar set of side effects.
To make the long journey, oral drugs must be dosed in very high concentration. One class of drugs, called carbonic anhydrase inhibitors (CAI), slow the formation of fluid by inhibiting a chemical reaction at the ciliary body. Along with their well-tested effectiveness comes nausea, tingling in fingers and toes, and other side effects. Oral drugs generally do not, however, cause side effects in the eye.
Certain topical drugs, while causing less systemic effects, on the other hand, can cause severe headaches and constrict the pupil, making the daytime appear dark.
In our grandparent application, analogs of 2-benzothiazole-sulfonamides are prepared as carbonic anhydrase inhibitors. While many of the compounds that are prepared are carbonic anhydrase active, in fact some have limited practical usage because the compounds are poorly soluble in water. This is not only true for certain carbonic anhydrase inhibitor active 2-benzothiazolesulfonamides, but it is also true for certain other carbonic anhydrase inhibitors such as methazolamide/acetazolamide analogs and dichlorphenamide analogs. Our parent application relates to prodrugs of these last three mentioned compounds.
Compounds which are carbonic anhydrase active inhibitors but have limited solubility in tears are, as a practical matter, of limited value in developing topical carbonic anhydrase inhibitors. Put another way, if the compound will not dissolve in the tears, its chances of penetrating the cornea to release the pharmacologically active carbonic anhydrase inhibitor are small, at best. Thus, it is important if one is developing effective carbonic anhydrase inhibitors which can be topically applied, that the compound be soluble in water and tears.
It is a primary objective of the present invention to provide carbonic anhydrase inhibitors with enhanced potency in comparison to methazolamide.
It is another objective of the present invention to prepare analogs of certain methazolamide carbonic anhydrase inhibitors. The drugs are soluble in tears, and can effectively penetrate the cornea and release the pharmacologically active carbonic anhydrase inhibitor by enzymatic and/or hydrolytic degradation of a chemical bond between a water soluble moiety and the carbonic anhydrase inhibitor.
The method and manner of accomplishing each of the above objectives as well as others will become apparent from the detailed description of the invention which follows hereinafter.